Abstract Cannabis could serve as a therapeutic alternative to opioids, however, preclinical studies using non-contingent THC pre-exposure and a recent epidemiological study indicate that cannabis use can increase the risk for future opioid abuse. Repeated drug exposure can lead to persistent hyper-reactivity to drugs and drug- associated stimuli. The underlying neuroadaptations of this sensitization are thought to be involved in increased drug seeking after chronic drug exposure. Cross-sensitization between drugs of abuse also occurs and some drugs cross-sensitize better than others, indicating distinct neuroadaptations depending on drug- class. However the neurobiological underpinnings of the enhanced responsiveness to heroin after THC pre- exposure are unknown. It has been shown that sensitization to morphine depends on MOR signaling in the Ventral pallidum (VP), however the lack of a preclinical model of chronic dual THC and heroin self- administration (SA) impedes a detailed investigation of THC-induced neuroadaptations within the reward pathway that could lead to cross-sensitization with opioids. I will employ a newly developed rat model of dual THC and heroin SA to study whether THC intake augments future heroin self-administration and cue-induced heroin seeking. I will investigate neuroadaptations in CB1R and MOR signaling in the VP after withdrawal from chronic THC and heroin exposure and will compare to adaptations induced by either chronic THC or heroin alone. I hypothesize that that THC and heroin exposure induce pathway specific adaptations in CB1 and MOR signaling which potentiate D1 afferents and inhibit D2 afferents in the VP and that these cross-adaptations contribute to facilitated cue-induced heroin seeking after THC pre-exposure.